The effects of elevated biliary pressures on bile formation and hepatic lipid metabolism will be examined in the rat. Although the obstructed biliary system leads to many metabolic and biochemical alterations, the sequence and progression of these changes are unclear. This proposal focuses on the role of increased biliary pressures in animals in which the enterohepatic circulation is intact. The objectives include assessing the changes in hepatic cholesterol and phospholipid synthesis as well as alterations in the secretion of these lipids and of bile salts at elevated biliary pressures. Canalicular secretion will be studied by 14C-erythritol clearances, and the relative sensitivity of the bile salt dependent flow and the bile salt independent flow to increased pressures will be determined. Cholesterol synthesis will be measured in vivo by observing the incorporation of radiolabel of 3H2O into cholesterol and in vitro by assaying microsomal HMGCoA reductase activity. The in vivo incorporation of 3H2O will also provide insight into the changes in the contribution of newly synthetized cholesterol to biliary cholesterol secretion and plasma cholesterol levels. The synthetic and secretory changes of cholesterol will be further observed in animals with elevated biliary pressures in which the bile salt pool will have been largely replaced by dehydrocholate. Changes in the plasma increment of cholesterol during the elevated pressure will also be studied in the setting of inhibition to cholesterol synthesis by 25-hydroxycholesterol. The data obtained will provide an understanding of the sequence of the earliest changes in lipid metabolism seen in obstructive disease.